Cyclodextrins are cyclic oligosaccharides obtained from starch, formed of six glucose units (α-cyclodextrin), seven glucose units (β-cyclodextrin) or eight glucose units (γ-cyclodextrin). They are known to form inclusion compounds with smaller molecules which fit entirely or at least partially into the 5–8 A cyclodextrin cavity, Saenger, W., “Cyclodextrin Inclusion Compounds in Research and Industry,” Angew. Chem. Int. Ed. Engl. 19, 344–362 (1980). α-cyclodextrin forms complexes with water, methanol, polyiodide, iodine, krypton, n-propanol, p-iodoaniline, dimethyl sulfoxide, methanol, m-nitrophenol, methyl orange, prostaglandin E, and potassium acetate; β-cyclodextrin forms complexes with water, n-propanol, p-iodophenol, 2,5-diiodobenzoic acid, and p-nitroacetanilide; and γ-cyclodextrin forms complexes with propanol/water and water. β-cyclodextrin is also known to increase stabilization of benzocaine, procaine, atropine, aspirin, nitroglycerin, allicin, phenylbutazone, salicyclic acid, ascaridole, the ether ester of chaulmoogric acid, linoleic acid and indomethacin. However, β-cyclodextrin has nephrotoxicity and membrane destabilizing properties. Because of the safety concerns with β-cyclodextrins, numerous chemical modifications of the cyclodextrins have been made. The different types of β-cyclodextrins are alkylated cyclodextrins, hydroxyalkylated cyclodextrins, carboxymethyl cyclodextrins and the sulfoalkylether cyclodextrins which include sulfobutylether (SBE) β-cyclodextrins, with degrees of substitution on 4 and 7 positions of β-cyclodextrin. The specific product in the last group includes Captisol®, an SBE 7-β-cyclodextrin (SBE-CD).
U.S. Pat. No. 4,596,795 discloses the administration of sex hormones, particularly testosterone, progesterone and estradiol in the form of their complexes or inclusions with specific derivatives of cyclodextrins by the sublingual or buccal route resulting in effective transfer of these hormones into the systemic circulation, followed by only gradual elimination.
U.S. Pat. No. 4,727,064 is directed to the method of conversion of drug compositions which themselves are crystalline and of low water-solubility into intrinsically amorphous complexes which have improved pharmaceutical properties. This conversion is achieved by inclusion of the above drug compositions into water-soluble, multi-component mixtures of cyclodextrin derivatives.
U.S. Pat. Nos. 5,134,127 and 5,376,645 disclose sulfoalkyl ether cyclodextrin derivatives and their use as solubilizing agents for water-insoluble drugs for oral, intranasal or parenteral administration.
U.S. Pat. No. 5,602,112 discloses pharmaceutical formulations containing an antiulcerative amount of a substituted cyclodextrin, an inherently water-soluble cytotoxic anti-cancer drug, and a sugar alcohol, such as mannitol. The cyclodextrin derivatives taught by this disclosure are used to ameliorate the ulcerative effects of the drugs and not to increase water-solubility because the drugs are inherently water-soluble. The sugar alcohol is added to enhance the ameliorative effect of the substituted cyclodextrin on the extravasation toxicity (ulceration) of the cytotoxic agents.
U.S. Pat. No. 6,218,375 discloses a ras-farnesyltransferase inhibitor complex comprising a compound having the formula I:
in combination with substituted cyclodextrins such as sulfobutylether-7-β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin. Although this complex has been found to be useful for treating cancer, there is a need in the art for FTI formulations having improved solubility, stability, and dissolution profiles that are suitable for parenteral use.